Vascular endothelial growth factor (VEGF) is also known as vascular permeability factor (VPF) because it increases capillary permeability to high molecular weight proteins. VEGF is produced by the periovulatory follicle and may play an important role in ovulation and neovascularization of the developing corpus luteum. It is also hypothesized that excessive VEGF production following multiple follicular development in in vitro fertilization-embryo transfer (IVF-ET) cycles contributes to ovarian hyperstimulation syndrome (OHSS) - a serious complication marked by transudation of protein-rich fluid from the vasculature into the abdominal cavity (acites), fluid and electrolyte problems, and even death. Therefore, a prospective study was designed to measure VEGF levels in serum and follicular fluid from women undergoing IVF-ET and to correlate VEGF levels with steroid concentrations, the initiation of pregnancy, and if possible, the occurrence of OHSS. Also, VEGF production by granulosa cells obtained at egg pickup for IVF was evaluated during culture. The results indicate that (a) levels of VEGF in follicular fluid or produced by cultured granulosa cells correlated positively with progesterone levels; moreover, VEGF concentrations in follicular fluid were 10-fold greater than in serum, (b) around the expected time of implantation (days 11-14 post-ET), serum levels of VEGF were higher in patients who became pregnant than those who did not, and (c) the highest levels of circulating VEGF were detected in one patient during the clinical onset and recurrence of OHSS symptoms. However, VEGF levels were low in women who became pregnant after receiving donated embryos during artificial cycles in which ovarian activity was suppressed by chronic GnRH-analog treatment. Thus, there appears to be a significant ovarian contribution to circulating VEGF levels, VEGF production by follicle cells is correlated with their degree of luteinization, and chorionic gonadotropin from the implanting embryo may increase luteal VEGF production. Finally, elevated VEGF levels may be a factor in the etiology of OHSS. A collaborative research proposal, as part of the U54 Center application, is planned to test further the hypothesis that excessive or aberrant expression of endothelial-specific vasoactive substances by the ovary is a cause of OHSS in IVF-ET protocols in infertile women.